Genetic influences on substance use and abuse vulnerability are well documented, however, neural and cognitive mechanisms mediating these genetic influences are little understood. Genetic epidemiological research suggests a common genetic liability to substance use, externalizing psychopathology, and impulsive personality traits. We hypothesize that genetic influences on addiction and comorbid psychopathology vulnerability are mediated by dysfunctional neurocognitive mechanisms of inhibitory self-regulation of behavior. The long-term goal of this study is to test this etiological pathway hypothesis through the implementation of a prospective longitudinal and genetically informative design with a theory-driven choice of experimental paradigms that tap into distinct "component processes" of cognitive control of behavior and have been linked to specific neural substrates in the prefrontal cortex. During the initial funding period, we have ascertained three consecutive birth-year cohorts of 12-year-old twins (n=755) and their parents (n=540). The twins are being followed up longitudinally with biannual comprehensive laboratory assessments including cognitive brain electrophysiology, behavioral tests, and diagnostic measures. During the original funding period, we examined developmental changes of key neurocognitive measures of behavioral regulation, established their heritability, and examined their relationships with behavioral characteristics. This renewal application seeks to extend longitudinal follow-up of the twin cohorts into late adolescence, particularly through the period of highest risk for initiation of substance use and abuse (ages 16-19). Specific aims will be 1) to examine developmental changes of the neural and cognitive mechanisms of inhibitory control and their genetic/environmental architecture during the transition from early to late adolescence and 2) to examine prospective developmental and genetic associations between neurocognitive predictors and behavioral outcomes, clarify their causal relationships, and evaluate the utility of inhibitory control measures as endophenotypes for addiction vulnerability. The proposed study will contribute to bridging the gap between genetics and complex behaviors and provide important neurocognitive endophenotypes for future genetic studies of drug abuse, as well as increase our understanding of etiological pathways to substance use and abuse in adolescence, which is essential to the development of better prevention and treatment methods. PUBLIC HEALTH RELEVANCE: A better understanding of genetic, developmental, and neurobiological factors increasing the propensity to substance use in adolescence can inform the development of more effective prevention and early intervention methods and thus contribute to reducing the burden of substance use disorders on society. Potential outcomes of this study can inform the development of behavioral and pharmacological treatment methods that are specifically tailored to adolescents and are based on the knowledge about the development of neurocognitive functions underlying impulsivity, risk taking, decision making, as well as individual differences in these processes and their genetic determinants.